ABSTRACT
This study aims to prepare nimodipine/tetramethylpyrazine-loaded poly(D, L-lactide-co-glycolide) dual-drug nanoparticles (NMD/TMP-NPs) and investigate pharmacokinetics and brain distribution to evaluate the possibility of enhancing the drug effect of dual-drug nanoparticles. NMD/TMP-NPs were prepared via W/O/W emulsion solvent evaporation. Entrapment efficiency and drug loading of NMD/TMP-NPs were investigated by ultracentrifugation, and drug release behavior in vitro was studied by dialysis method. The pharmacokinetic and brain distribution were studied in SD mice administered intravenously with NMD/TMP-NPs in comparison with NMD-suspension, NMD/TMP-suspension and NMD-NPs, (NMD-NPs+TMP)-suspension. According to the results, the entrapment efficiency and drug loading of NMD were (79.71±0.73)%, (1.74±0.02)%, those of TMP were (40.26±1.51)% and (4.38±0.16)%. The nanoparticles showed the property of sustained release. On the basis of the major parameters for in vivo pharmacokinetic and brain distribution, t1/2β of NMD-suspension, NMD/TMP-suspension and NMD-NPs, (NMD-NPs+TMP)-suspension, NMD/TMP-NPs were (1.097±0.146), (1.055±0.06), (1.950±0.140), (1.860±0.096), (2.497±0.475） h, CL were (0.778±0.098), (1.133±0.111), (0.247±0.023), (0.497±0.040), (0.297±0.024) h•L-1, AUC0-t in rat plasma were (514.218±60.383), (352.916±33.691), (1 618.429±240.198), (804.110±75.804), (1 349.058±215.497) μg•h•L⁻¹, respectively, and AUC0-t in brain were 0.301 9, 0.624 8, 1.068 6, 1.313 0, 1.046 5 mg•h•L⁻¹, respectively. According to the in vivo study, the pharmacokinetic behavior of NMD were markedly prolonged by adding TMP or prepared dual-drug nanoparticles.
ABSTRACT
OBJECTIVE: To prepare nimodipine/tetramethylpyrazine-loaded poly[poly (lactic-co-glycolic acid), PLGA] dual-drug nanoparticles (nimodipine/tetramethylpyrazine-PLGA-nanoparticles, NMD/TMP-PLGA-NPs), and investigate the in vitro release behavior and brain distribution. METHODS: NMD/TMP-PLGA-NPs were prepared by optimized emulsion solvent evaporation method with PLGA as a carrier material; the morphology of NMD/TMP-PLGA-NPs was observed by transmission electron microscope; the mean particle size, particle size distribution and Zeta potential were measured by laser particle size analyzer; the entrapment efficiency and drug loading were measured by ultracentrifugation; the in vitro release behavior was studied by dialysis; the brain distribution was compared with NMD-suspension and NMD-PLGA-NPs. RESULTS: The NMD/TMP-PLGA-NPs were spherical; the mean particle size, particle size distribution and Zeta potential of NPs were (631.60±3.20) nm, (0.097±0.007), (-29.25±1.87) mV, respective-ly. The entrapment efficiency and drug loading of NMD were (76.25±1.18)% and (1.24±0.01)%, while those of TMP were (39.30±1.00)% and (6.34±0.11)%, respectively. The profiles of in vitro release had the features of sustained release. The ALC0→t of NMD-suspension, NMD-PLGA-NPs and NMD/TMP-PLGA-NPs were 0.2683, 0.4596 and 0.8815 μg·min·mL-1, and the addition of TMP promoted the reach of highest brain concentration. CONCLUSION: NMD/TMP-PLGA-NPs are prepared successfully and show sustained-release in vitro, and the distribution of NMD into brain was increased significantly with the addition of TMP.